ISSN:
1432-1912
Keywords:
CGP 28014
;
COMT inhibition
;
Parkinson's disease
;
Tropolone
;
Pyrogallol
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary CGP 28014 (N-(2-pyridone-6-yl)-N′,N′-di-n-propylformamidine) or its methanesulfonate salt CGP 28014 A was suspected to be a catechol-O-methyl-transferase (COMT) inhibitor because it was found to reduce the levels of homovanillic acid (HVA) and to increase those of 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat striatum, after oral or intraperitoneal administration. These effects were maintained after repeated administration. The compound was only weakly active as a COMT inhibitor in vitro. However, its effect on striatal HVA and DOPAC was not prevented by pretreatment with the inhibitor of microsomal drug metabolizing enzymes in the liver, proadifen, indicating that, if CGP 28014 acts as a prodrug, its conversion to the active compound is not by oxidative metabolism in the liver. Also, there was no evidence that conversion to 2-amino-6-hydroxypyridine could explain its effects. The in vivo effect of CGP 28014 was substantiated in two additional in vivo test systems. Thus, it inhibited the accumulation of 3-methoxytyramine in the rat striatum after MAO inhibition by clorgyline, and the formation of O-methyl-DOPA from exogenously administered DOPA. It proved to be equipotent or nearly so with tropolone, and also showed a similar duration of action. Similar to tropolone, it increased S-adenosylmethionine levels in the striatum. Pyrogallol, on the other hand, decreased them, because being a substrate of COMT, it consumes methyl groups. This suggests that CGP 28014 does not inhibit COMT because it is a substrate of the enzyme. No effects were noted on catecholamine and serotonin concentrations in rat brain; no effects on noradrenaline uptake in rat heart, or on serotonin uptake in rat brain at doses of 30 mg/kg i.p. and above were found. Slight increases of brain tryptophan and 5-hydroxyindoleacetic acid, found occasionally, may indicate a minimal enhancing effect on serotonin turnover. In receptor binding tests, CGP 28014 at 10−5 mol/l showed very weak or no interactions at all with αl-, α2-and ß-noradrenergic, 5-HT1A, 5-HT1B, 5-HT2, muscarinic cholinergic, histamine, H1 and H2, GABAA, benzodiazepine, adenosine A1 and A2, δ-, µ- and κ-opiate, and substance P receptors in vitro, and D2 and 5-HT2 receptors in vivo. The compound holds a potential to improve the efficacy of L-DOPA in the treatment of parkinsonism.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00169442
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